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Abstract:

The invention relates to the use of a combination of protein tyrosine
phosphatase inhibitors and human growth hormone for the treatment of
musculoskeletal diseases, particularly for the treatment of muscle
atrophy.

Claims:

1. A method of treating a musculoskeletal disease, comprisingidentifying
an individual exhibiting the musculoskeletal disease or at risk for
developing the musculoskeletal disease; andadministering to the
individual a therapeutically effective amount of a PTP inhibitor in
combination with human growth hormone sufficient to alleviate the
musculoskeletal disease.

2. (canceled)

3. The method of claim 1, wherein the musculoskeletal disease is muscle
atrophy.

4. The method of claim 3, wherein the muscle atrophy is a result of
treatment with a glucocorticoid.

12. The method of claim 1, wherein the musculoskeletal disease is
osteoporosis, a bone fracture, short stature, or dwarfism.

13. The method of claim 1 wherein the PTP inhibitor is a compound of the
formula ##STR00024## whereinQ combined together with the carbon atoms to
which it is attached form an aromatic, or a partially or fully saturated
nonaromatic 5- to 8-membered carbocyclic or heterocyclic ring;R1 is
hydrogen, --C(O)R6, --C(O)NR7R9 or --C(O)OR9 in
whichR6 and R7 are, independently from each other, hydrogen,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R8 and R9 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2, R3, R4 and R5 are, independently
from each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy,
alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,
sulfamoyl, optionally substituted amino, cycloalkyl, aryl, heterocyclyl,
alkenyl, alkynyl or (C1-8)alkyl optionally substituted with one to
four substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, aryloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2 and R3
combined are alkylene which together with the ring atoms to which they
are attached form a 3- to 7-membered fused ring; orR2 and R3
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered spirocyclic ring;or a
pharmaceutically acceptable salt thereof.

14. The method of claim 1, wherein the PTP inhibitor is a compound of the
formula ##STR00025## whereinR1 is hydrogen, --C(O)R2,
--C(O)NR3R4 or --C(O)OR5 in whichR2 and R3 are,
independently from each other, hydrogen, cycloalkyl, aryl, heterocyclyl,
aralkyl, heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R4 and R5 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;U, W and V are, independently from each other, hydrogen,
hydroxy, halogen, cyano, nitro, alkoxy, alkylthio, alkylthiono, sulfonyl,
free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted
amino, cycloalkyl, aryl, aryloxy, arylthio, heterocyclyl,
heterocycloyloxy, alkenyl, alkynyl or (C1-8)alkyl optionally
substituted with one to four substituents selected from the group
consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy,
alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, acylamino,
carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido,
sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy,
arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and
heterocyclyloxy; orU and W combined together with the carbon atoms to
which they are attached form an optionally substituted aromatic, or a
partially or fully saturated nonaromatic 5- to 8-membered carbocyclic or
heterocyclic ring; orW and V combined together with the carbon atoms to
which they are attached form an optionally substituted aromatic, or
partially or fully saturated nonaromatic 5- to 8-membered carbocyclic or
heterocyclic ring;or a pharmaceutically acceptable salt thereof.

15. The method of claim 1, wherein the PTP inhibitor is a compound of the
formula ##STR00026## whereinR1 is hydrogen, --C(O)R5,
--C(O)NR6R7 or --C(O)OR8 in whichR5 and R6 are,
independently from each other, hydrogen, cycloalkyl, aryl, heterocyclyl,
aralkyl, heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R7 and R8 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2, R3 and R4 are, independently from each
other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio,
alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,
optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl,
alkynyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2 and R3
combined are alkylene which together with the ring atoms to which they
are attached form a 5- to 7-membered fused ring provided R2 and
R3 are attached to carbon atoms adjacent to each other; orR2
and R3 combined together with the carbon atom to which they are
attached form a fused 5- to 6-membered aromatic or heteroaromatic ring
provided R2 and R3 are attached to carbon atoms adjacent to
each other;X is hydrogen, fluoro, cyano, or free or esterified carboxy;
orX is --NR9C(O)R10, --NR9C(O)OR11,
--NR9S(O)2R12, --(CH2)mS(O)2R13,
--OS(O)2R14 or --OnC(O)NR15R16 in whichR9
is hydrogen, lower alkyl, acyl, alkoxycarbonyl or sulfonyl;R10,
R11, R12, R13 and R14 are, independently from each
other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or
(C1-8)alkyl optionally substituted with one to four substituents
selected from the group consisting of halogen, hydroxy, cycloalkyl,
cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino, alkylamino,
dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono,
sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or esterified
carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR10, R12
and R13 are, independently from each other, --NR12R18 in
whichR17 and R18 are, independently from each other, hydrogen,
alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl; orR17 and R18
combined are alkylene which together with the nitrogen atom to which they
are attached form a 4- to 7-membered ring;R15 and R16 are,
independently from each other, hydrogen, alkyl, cycloalkyl, aralkyl, aryl
or heterocyclyl; orR15 and R16 combined are alkylene which
together with the nitrogen atom to which they are attached form a 4- to
7-membered ring;m and n are, independently from each other, zero or an
integer of 1; orC--X is replaced by nitrogen;Y is CH2, O or S;or a
pharmaceutically acceptable salt thereof.

17. The method of claim 1, wherein the PTP inhibitor is a compound of the
formula ##STR00028## whereinQ is:i) --X, orii)
--Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X in
which;Y is oxygen or S(O)q in which q is zero or an integer of 1 or
2; orY is --C≡C-- or --C═C--; orY is cyclopropyl orY is
absent;n and m are, independently from each other, zero or an integer
from 1 to 8;R8 and R9 are, independently from each other,
hydrogen, hydroxyl, alkoxy, alkanoyl, alkanoylamino, alkoxycarbonyl,
aralkyl, heteroaryl, carbamoyl, aryl, or alkyl; orR8 and R9
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered ring;p is zero or an integer
selected from 1 or 2Z is absent;Z is --C(O)--O--; orZ is --C(O)--; orZ is
--C(O)--NRα-alkylene- or --C(O)--NRα-alkylene-O--, wherein
Rα is H or lower alkyl; orZ is
--CO--NRα-(CH2)n'(CR8'R9')p'--(CH2).s-
ub.m'--, or
--C(O)--NRα-(CH2)n'--(CR8'R9')p'--(CH2)m'--O--, wherein p' is zero or an integer of 1, n' and m' are,
independently from each other, zero or an integer from 1 to 8, R8'
and R9' are, independently from each other, hydrogen or lower alkyl,
Rquadrature is H or lower alkyl; orZ is --NRα'-C(O)--, or
--NRα'-C(O)--O--, wherein Rα' is H or lower alkyl, or
Rα' and R9 combined are alkylene which together with the
carbon atom to which they are attached form a 3- to 7-membered ring; orZ
is --C(O)--NH--NH--C(O)--O--; orZ is --S(O)2--, or --S(O)--; orZ is
--NRβ-S(O)2--, wherein Rβ is H, lower alkyl, or Rβ
and R9 combined are alkylene which together with the carbon atom to
which they are attached form a 3- to 7-membered ring; orZ is
--NH--S(O)2--NH--C(O)--O--; orZ is --NRγ--C(O)--NRγ'--;
wherein Rγ' is H, alkyl, aryl, heterocyclyl, or lower alkoxy and
Rγ is H, lower alkyl, or Rγ and R9 combined are alkylene
which together with the carbon atom to which they are attached form a 3-
to 7-membered ring; or Rγ' and X combined are alkylene which
together with the carbon atom to which they are attached form a 3- to
7-membered ring orZ is --NRτ-C(O)--NH--S(O)2--, wherein Rτ
is H or lower alkyl,X is hydrogen, hydroxy, NH2, halogen, alkoxy,
alkylthio, alkyl, --S(O)--OH, alkyl, cycloalkyl, cycloalkoxy, acyl,
acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl,
free or esterified carboxy, heterocyclyl, heterocyclooxy, heteroaryl,
heteroaralkyl, aryl, aralkyl, aralkoxy, aryloxy, aralkylthio,
arylthio;R1 is hydrogen, --C(O)R4, --C(O)NR5R6 or
--C(O)OR7 in whichR4 and R6 are, independently from each
other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R6 and R2 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2 and R3 are, independently from each other,
hydrogen, halogen, (C1-3)alkyl or (C1-3)alkoxy;or a
pharmaceutically acceptable salt thereof,and wherein n+m+p is >1 or is
0, when X is aryl, and Y and Z are absent,n+m+p is not 0 when X is
--O-aryl, and Y and Z are absent, orn+m+p is not 0 when X is --S-aryl,
and Y and Z are absent orn+m+p is not 0 when X is --CH2-aryl, and Y
and Z are absent, orn+m+p is not 0 when X is aryl, Z is absent and Y is
--O-- or Y is --S--, orwherein Q cannot be --CH2-aryl, --S-aryl or
--O-aryl.

18. The method of claim 1, further comprising administering an IGF1
molecule to the individual.

19. (canceled)

20. A method of increasing muscle or bone mass in an individual, the
method comprisingidentifying an individual in which increasing muscle or
bone mass is desirable; andadministering to the individual an amount of a
PTP inhibitor sufficient to increase the muscle or bone mass in the
individual.

23. The composition according to claim 22, wherein the protein tyrosine
phosphatase inhibitor compound and human growth hormone are a fixed
single dosage composition.

24. The composition according to claim 22, wherein the protein tyrosine
phosphatase inhibitor compound and human growth hormone are administered
sequentially or concurrently.

Description:

[0001]The invention relates to compounds that inhibit protein tyrosine
phosphatase (PTP), particularly PTP-1B, in combination with human growth
hormone and the combinations use in the treatment of musculoskeletal
disease.

[0002]Cellular signal transduction is a fundamental mechanism whereby
external stimuli that regulate diverse cellular processes are relayed to
the interior of cells. One of the key biochemical mechanisms of signal
transduction involves the reversible phosphorylation of proteins, which
enables regulation of the activity of mature proteins by altering their
structure and function. The best characterized protein kinases in
eukaryotes phosphorylate proteins on the alcohol moiety of serine,
threonine and tyrosine residues. These kinases largely fall into two
groups, those specific for phosphorylating serines and threonines, and
those specific for phosphorylating tyrosines.

[0003]The phosphorylation state of a given substrate is also regulated by
protein phosphatases, a class of proteins responsible for removal of the
phosphate group added to a given substrate by a protein kinase. The
protein phosphatases can also be classified as being specific for either
serine/threonine or tyrosine. The known enzymes can be divided into two
groups--receptor and non-receptor type proteins. Most receptor-type
protein tyrosine phosphatases (RPTPs) contain two conserved catalytic
tyrosine phosphatase domains each of which encompasses a segment of 240
amino acid residues (Saito et al., Cell Growth and Diff. 2:59-65, 1991).
The RPTPs can be subclassified further based upon the amino acid sequence
diversity of their extracellular domains (Saito, et al., supra; Krueger,
et al., Proc. Natl. Acad. Sci. USA 89:7417-7421, 1992). Alignment of
primary peptide sequences of both types of known PTPs shows some sequence
consensus in catalytic domains and has made it possible to identify cDNAs
encoding proteins with tyrosine phosphate activity via the polymerase
chain reaction (PCR).

[0004]Many kinases and phosphatases are involved in regulatory cascades
wherein their substrates may include, but are not limited to, other
kinases and phosphatases whose activities are regulated by their
phosphorylation state. Ultimately the activity of some downstream
effector is modulated by phosphorylation resulting from activation of
such a pathway.

[0005]It is well established that the abnormal or inappropriate activity
of tyrosine kinases and/or tyrosine phosphatases plays a role in a
variety of human disorders including cell proliferative disorders such as
cancer, fibrotic disorders, disorders of the immune system and metabolic
disorders such as diabetes.

[0006]The invention is based on the discovery that PTP inhibitors in
combination with human growth hormone can be used to treat
musculoskeletal diseases or conditions, particularly muscle atrophy, in a
mammal such as a human individual or patient. Accordingly, the invention
includes a method of treating a musculoskeletal disease by identifying an
individual exhibiting the musculoskeletal disease or at risk for
developing the musculoskeletal disease and administering to the
individual a therapeutically effective amount of a PTP inhibitor in
combination with human growth hormone sufficient to alleviate the
musculoskeletal disease. The invention also includes the use of a PTP
inhibitor in combination with human growth hormone in the manufacture of
a medicament for the treatment or prevention of a musculoskeletal
disease. In addition, the invention includes use of PTP inhibitors in
combination with human growth hormone to increase muscle or bone mass in
an individual, whether or not such an individual is at risk for or has a
musculoskeletal disease. In general terms the invention relates to a kit
comprising sequential or concurrent daily dosage units for administration
each active ingredient. The combination of protein tyrosine phosphatase
inhibitor compound and human growth hormone may be a fixed dosage.

[0007]In particular, the musculoskeletal disease can be muscle atrophy.
There are many causes of muscle atrophy, including as a result of
treatment with a glucocorticoid such as cortisol, dexamethasone,
betamethasone, prednisone, methylprednisolone, or prednisolone. The
muscle atrophy can also be a result of denervation due to nerve trauma or
a result of degenerative, metabolic, or inflammatory neuropathy (e.g.,
Guillian-Barre syndrome, peripheral neuropathy, or exposure to
environmental toxins or drugs). In addition, the muscle atrophy can be a
result of an adult motor neuron disease, infantile spinal muscular
atrophy, juvenile spinal muscular atrophy, autoimmune motor neuropathy
with multifocal conductor block, paralysis due to stroke or spinal cord
injury, skeletal immobilization due to trauma, prolonged bed rest,
voluntary inactivity, involuntary inactivity, metabolic stress or
nutritional insufficiency, cancer, AIDS, fasting, rhabdomyolysis, a
thyroid gland disorder, diabetes, benign congenital hypotonia, central
core disease, nemalene myopathy, myotubular (centronuclear) myopathy,
burn injury, chronic obstructive pulmonary disease, liver disease,
sepsis, renal failure, congestive heart failure, or ageing.

[0008]The musculoskeletal disease can also be a muscular dystrophy
syndrome, such as Duchenne, Becker, myotonic, fascioscapulohumeral,
Emery-Deifuss, oculopharyngeal, scapulohumeral, limb girdle, a congenital
muscular dystrophy, or hereditary distal myopathy. The musculoskeletal
disease can also be osteoporosis, a bone fracture, short stature, or
dwarfism.

[0009]Any suitable PTP inhibitor, such as described in the next section,
can be used to treat the above-mentioned musculoskeletal diseases. Since
it is known that administration of human Growth Hormone has beneficial
effects on the musculoskeletal system by up regulating the insulin-like
growth factor pathway, human Growth Hormone can be co-administered along
with the PTP inhibitor in the methods of the invention

[0010]All cited references or documents are hereby incorporated by
reference.

BRIEF DESCRIPTION OF THE DRAWING

[0011]FIG. 1 shows results from an experiment where WT and KO mice had
their right leg denervated by sciatic nerve resection.

[0012]The invention relates to the treatment of musculoskeletal diseases,
in particular muscle atrophy, low bone density or mineral content, and
short stature. Any PTP inhibitor can be used in the methods of the
invention, for example, the inhibitors described in US patents and patent
application publications U.S. Pat. Nos. 7,115,624; 7,078,425; 7,022,730;
6,911,468; and 2005/0090502. In addition, specific inhibitors of PTP,
particularly PTP-1B and T-cell PTP, can include the categories of
compounds and specific compounds therein, as described below.
Pharmaceutically acceptable human growth hormone (hGH) or a
pharmaceutical equivalent is the second main component.

[0013]Listed below are definitions of various terms used to describe the
compounds of the instant invention. These definitions apply to the terms
as they are used throughout the specification unless they are otherwise
limited in specific instances either individually or as part of a larger
group. In general, whenever an alkyl group is referred to as a part of
the structure, an optionally substituted alkyl is also intended.

[0015]The term "lower alkyl" refers to any of the above alkyl groups as
described above having 1 to 7, preferably 1 to 4 carbon atoms.

[0016]The term "halogen" or "halo" refers to fluorine, chlorine, bromine
and iodine.

[0017]The term "alkenyl" refers to any of the above alkyl groups having at
least 2 carbon atoms and containing a carbon to carbon double bond at the
point of attachment. Groups having 2 to 8 carbon atoms are preferred.

[0018]The term "alkynyl" refers to any of the above alkyl groups having at
least two carbon atoms and containing a carbon to carbon triple bond at
the point of attachment. Groups having 2 to 8 carbon atoms are preferred.

[0020]The term "cycloalkyl" refers to optionally substituted monocyclic,
bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, each of
which may be substituted by one or more substituents such as alkyl, halo,
oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino,
dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the
like.

[0038]The term "sulfonyl" refers to alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

[0039]The term "sulfonate" or "sulfonyloxy" refers to
alkyl-S(O)2--O--, aryl-S(O)2--O--, aralkyl-S(O)2--O--,
heteroaryl-S(O)2--O--, heteroaralkyl-S(O)2--O-- and the like.

[0040]The term "optionally substituted amino" refers to a primary or
secondary amino group which may optionally be substituted by a
substituent such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,
heteroaralkoxycarbonyl, carboxycarbonyl, carbamoyl,
alkylaminothiocarbonyl, arylaminothiocarbonyl and the like.

[0041]The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such
as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups,
each of which may optionally be substituted by one to five substituents
such as alkyl, trifluoromethyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy,
optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl,
sulfonamido, sulfonate, heterocyclyl and the like.

[0042]The term "monocyclic aryl" refers to optionally substituted phenyl
as described under aryl.

[0043]The term "aralkyl" refers to an aryl group bonded directly through
an alkyl group, such as benzyl.

[0044]The term "aralkanoyl" refers to aralkyl-C(O)--.

[0045]The term "aralkylthio" refers to aralkyl-S--.

[0046]The term "aralkoxy" refers to an aryl group bonded directly through
an alkoxy group.

[0047]The term "arylsulfonyl" refers to aryl S(O)2.

[0048]The term "arylthio" refers to aryl-S--.

[0049]The term "aroyl" refers to aryl-C(O)--.

[0050]The term "aroylamino" refers to aryl-C(O)--NH--.

[0051]The term "aryloxycarbonyl" refers to aryl-O--C(O)--.

[0052]The term "heterocyclyl" or "heterocyclo" refers to an optionally
substituted, aromatic, or a partially or fully saturated nonaromatic
cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to
12-membered bicyclic, or 10- to 15-membered tricyclic ring system, which
has at least one heteroatom in at least one carbon atom containing ring.
Each ring of the heterocyclic group containing a heteroatom may have 1, 2
or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur
atoms, where the nitrogen and sulfur heteroatoms may also optionally be
oxidized. The heterocyclic group may be attached at a heteroatom or a
carbon atom.

[0056]The term "heterocyclyl" includes substituted heterocyclic groups.
Substituted heterocyclic groups refer to heterocyclic groups that are
substituted with 1, 2 or 3 substituents selected from the group
consisting of the following:

[0069]Pharmaceutically acceptable salts of any compound useful in the
present invention refer to salts formed with bases, namely cationic salts
such as alkali and alkaline earth metal salts, such as sodium, lithium,
potassium, calcium, magnesium, as well as ammonium salts, such as
ammonium, trimethylammonium, diethylammonium, and
tris(hydroxymethyl)-methylammonium salts, and salts with amino acids.

[0070]Similarly acid addition salts, such as those formed with mineral
acids, organic carboxylic acids and organic sulfonic acids e.g.
hydrochloric acid, maleic acid and methanesulfonic acid, are possible
provided a basic group, such as pyridyl, constitutes part of the
structure.

[0071]In starting compounds and intermediates which are converted to the
compounds useful in the invention in a manner described herein,
functional groups present, such as amino, thiol, carboxyl, and hydroxy
groups, are optionally protected by conventional protecting groups that
are common in preparative organic chemistry. Protected amino, thiol,
carboxyl, and hydroxyl groups are those that can be converted under mild
conditions into free amino thiol, carboxyl and hydroxyl groups without
the molecular framework being destroyed or other undesired side reactions
taking place.

[0072]The purpose of introducing protecting groups is to protect the
functional groups from undesired reactions with reaction components under
the conditions used for carrying out a desired chemical transformation.
The need and choice of protecting groups for a particular reaction is
known to those skilled in the art and depends on the nature of the
functional group to be protected (hydroxyl group, amino group, etc.), the
structure and stability of the molecule of which the substituent is a
part and the reaction conditions. Well known protecting groups that meet
these conditions and their introduction and removal are described, for
example, in McOmie, "Protective Groups in Organic Chemistry", Plenum
Press, London, New York (1973); and Greene and Wuts, "Protective Groups
in Organic Synthesis", John Wiley and Sons, Inc, New York (1999).

[0073]The above mentioned reactions are carried out according to standard
methods, in the presence or absence of diluent, preferably such as are
inert to the reagents and are solvents thereof, of catalysts, condensing
or said other agents respectively and/or inert atmospheres, at low
temperatures, room temperature or elevated temperatures (preferably at or
near the boiling point of the solvents used), and at atmospheric or
super-atmospheric pressure.

[0074]The invention further includes any variant of the present processes,
in which an intermediate product obtainable at any stage thereof is used
as starting material and the remaining steps are carried out, or in which
the starting materials are formed in situ under the reaction conditions,
or in which the reaction components are used in the form of their salts
or optically pure antipodes.

[0075]Compounds useful in the invention and intermediates can also be
converted into each other according to methods generally known per se.

[0076]Depending on the choice of starting materials and methods, the
compounds may be in the form of one of the possible isomers or mixtures
thereof, for example, as substantially pure geometric (cis or trans)
isomers, optical isomers (enantiomers, antipodes), racemates, or mixtures
thereof. The aforesaid possible isomers or mixtures thereof are within
the purview of this invention.

[0077]Any resulting mixtures of isomers can be separated on the basis of
the physico-chemical differences of the constituents, into the pure
geometric or optical isomers, diastereoisomers, racemates, for example by
chromatography and/or fractional crystallization.

[0078]Any resulting racemates of final products or intermediates can be
resolved into the optical antipodes by known methods, e.g. by separation
of the diastereoisomeric salts thereof, obtained with an optically active
acid or base, and liberating the optically active acidic or basic
compound. The carboxylic acid intermediates can thus be resolved into
their optical antipodes e.g. by fractional crystallization of D- or
L-(alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine,
ephedrine, dehydroabietylamine, brucine or strychnine)-salts. Racemic
products can also be resolved by chiral chromatography, e.g. high
pressure liquid chromatography using a chiral adsorbent.

[0079]Finally, compounds useful in the invention are either obtained in
the free form, as a salt thereof if salt forming groups are present or as
prodrug derivatives thereof. In particular, the NH-group of the
1,1-dioxo-1,2,5-thiadiazolidin-3-one moiety, may be converted into salts
with pharmaceutically acceptable bases. Salts may be formed using
conventional methods, advantageously in the presence of an ethereal or
alcoholic solvent, such as a lower alkanol. From the solutions of the
latter, the salts may be precipitated with ethers, e.g. diethyl ether.
Resulting salts may be converted into the free compounds by treatment
with acids. These or other salts can also be used for purification of the
compounds obtained.

[0080]Compounds useful in the invention having basic groups can be
converted into acid addition salts, especially pharmaceutically
acceptable salts. These are formed, for example, with inorganic acids,
such as mineral acids, for example sulfuric acid, a phosphoric or
hydrohalic acid, or with organic carboxylic acids, such as
(C1-4)alkanecarboxylic acids which, for example, are unsubstituted
or substituted by halogen, for example acetic acid, such as saturated or
unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or
fumaric acid, such as hydroxy-carboxylic acids, for example glycolic,
lactic, malic, tartaric or citric acid, such as amino acids, for example
aspartic or glutamic acid, or with organic sulfonic acids, such as
(C1-4)alkyl-sulfonic acids (for example methanesulfonic acid) or
arylsulfonic acids which are unsubstituted or substituted (for example by
halogen). Preferred are salts formed with hydrochloric acid,
methanesulfonic acid and maleic acid.

[0081]Prodrug derivatives of any compound of the present invention are
derivatives of said compounds which following administration release the
parent compound in vivo via some chemical or physiological process, e.g.,
a prodrug on being brought to the physiological pH or through enzyme
action is converted to the parent compound. Exemplary prodrug derivatives
are, e.g., esters of free carboxylic acids and S-acyl and O-acyl
derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as
defined herein. Preferred are pharmaceutically acceptable ester
derivatives convertible by solvolysis under physiological conditions to
the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters,
lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl
esters, such as the ω-(amino, mono- or di-lower alkylamino,
carboxy, lower alkoxycarbonyl)-lower alkyl esters, the α-(lower
alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower
alkyl esters, such as the pivaloyloxymethyl ester and the like
conventionally used in the art.

[0082]In view of the close relationship between the free compounds, the
prodrug derivatives and the compounds in the form of their salts,
whenever a compound is referred to in this context, a prodrug derivative
and a corresponding salt is also intended, provided such is possible or
appropriate under the circumstances.

[0083]The compounds, including their salts, can also be obtained in the
form of their hydrates, or include other solvents used for their
crystallization.

[0084]Thus, the pharmacologically active compounds useful in the invention
may be employed in the manufacture of pharmaceutical compositions
comprising an effective amount thereof in conjunction or admixture with
excipients or carriers suitable for either enteral or parenteral
application. Preferred are tablets and gelatin capsules comprising the
active ingredient together with:

[0085]Said compositions may be sterilized and/or contain adjuvants, such
as preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to conventional
mixing, granulating or coating methods, respectively, and contain about
0.1-75%, preferably about 1-50%, of the active ingredient.

[0086]Suitable formulations for transdermal application include a
therapeutically effective amount of a compound of the invention with
carrier. Advantageous carriers include absorbable pharmacologically
acceptable solvents to assist passage through the skin of the host.
Characteristically, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to
deliver the compound of the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to secure
the device to the skin.

[0087]The pharmaceutical compositions useful in the invention may contain
a therapeutically effective amount of a compound as defined above with
human growth hormone, in a combination with another therapeutic agent,
e.g., each at an effective therapeutic dose as reported in the art. One
such compound that can be administered along with the PTP inhibitor is
human insulin-like growth factor1 or IGF1, however formulated or
stabilized, such as INCRELEX® as developed by Tercica or as described
in US 2006/0166328.

[0088]The structure of the therapeutic agents identified by code numbers,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g., Patents
International (e.g. IMS World Publications).

[0089]As used throughout the specification and in the claims, the term
"treatment" embraces all the different forms or modes of treatment as
known to those of the pertinent art and in particular includes
preventive, curative, delay of progression and palliative treatment.

[0090]The above-cited properties are demonstrable in vitro and in vivo
tests, using advantageously mammals, e.g., mice, rats, dogs, monkeys or
isolated organs, tissues and preparations thereof. Said compounds can be
applied in vitro in the form of solutions, e.g. preferably aqueous
solutions, and in vivo either enterally, parenterally, advantageously
intravenously, e.g. as a suspension or in aqueous solution. The dosage in
vitro may range between about 10-3 molar and 10-10 molar
concentrations. A therapeutically effective amount in vivo may range
depending on the route of administration, between about 1 and 500 mg/kg,
preferably between about 5 and 100 mg/kg.

[0091]The activity of a compound according to the invention may be
assessed by the following methods or by following methods well described
in the art (e.g. Peters G. et al. J. Biol. Chem., 2000, 275, 18201-09).

[0092]For example, the PTP-1B inhibitory activity in vitro may be
determined as follows:

[0093]Assessment of human PTP-1B (hPTP-1B) activity in the presence of
various agents is determined by measuring the amount of inorganic
phosphate released from a phosphopeptide substrate using a 96-well
microtiter plate format. The assay (100 μL) is performed in an assay
buffer comprised of 50 mM TRIS (pH 7.5), 50 mM NaCl, 3 mM DTT at ambient
temperature. The assay is typically performed in the presence of 0.4%
dimethyl sulfoxide (DMSO). However, concentrations as high as 10% are
used with certain poorly soluble compounds. A typical reaction is
initiated by the addition of 0.4 pmoles of hPTP-1B (amino acids 1-411) to
wells containing assay buffer, 3 nmoles of the synthetic phosphopeptide
substrate (GNGDpYMPMSPKS), and the test compound. After 10 min, 180 μL
malachite green reagent (0.88 mM malachite green, 8.2 mM ammonium
molybdate, aqueous 1 N HCl, and 0.01% Triton X-100) is added to terminate
the reaction. Inorganic phosphate, a product of the enzyme reaction, is
quantitated after 15 min as the green color resulting from complexing
with the Malichite reagent and is determined as an A620 using a
Molecular Devices (Sunnyvale, Calif.) SpectraMAX Plus spectrophotometer.
Test compounds are solubilized in 100% DMSO (Sigma, D-8779) and diluted
in DMSO. Activity is defined as the net change in absorbance resulting
from the activity of the uninhibited hPTP-1B.sub.[1-411] minus that of a
tube with acid-inactivated hPTP-1B.sub.[1-411].

[0094]The hPTP-1B.sub.[1-411] is cloned by PCR from a human hippocampal
cDNA library (Clonetech) and inserted into a pET 19-b vector (Novagen) at
the Nco1 restriction site. E. coli strain BL21 (DE3) is transformed with
this clone and stored as a stock culture in 20% glycerol at -80°
C. For enzyme production, a stock culture is inoculated into LB/Amp and
grown at 37° C. Expression of PTP-1B is initiated by induction
with 1 mM IPTG after the culture had reached an OD600=0.6. After 4
h, the bacterial pellet is collected by centrifugation. Cells are
resuspended in 70 mL lysis buffer (50 mM Tris, 100 mM NaCl, 5 mM DTT,
0.1% Triton X-100, pH7.6), incubated on ice for 30 min then sonicated
(4×10 sec bursts at full power). The lysate is centrifuged at
100,000×g for 60 min and the supernatant is buffer exchanged and
purified on a cation exchange POROS 20SP column followed by an anion
exchange Source 30Q (Pharmacia) column, using linear NaCl gradient
elutions. Enzyme is pooled, adjusted to 1 mg/mL and frozen at -80°
C.

[0095]Alternatively, the assessment of human PTP-1B activity in the
presence of various agents may be determined by measuring the hydrolysis
products of known competing substrates. For example, cleavage of
substrate para-nitrophenylphosphate (pNPP) results in the release of the
yellow-colored para-nitrophenol (pNP) which can be monitored in real time
using a spectrophotometer. Likewise, the hydrolysis of the fluorogenic
substrate 6,8-difluoro-4-methylumbelliferyl phosphate ammonium salt
(DiFMUP) results in the release of the fluorescent DiFMU which can be
readily followed in a continuous mode with a fluorescence reader (Anal.
Biochem. 273, 41, 1999; Anal. Biochem. 338, 32, 2005):

pNPP Assay

[0096]Compounds are incubated with 1 nM recombinant human
PTP-1B.sub.[1-298] or PTP-1B.sub.[1-322] in buffer (50 mM Hepes, pH 7.0,
50 mM KCl, 1 mM EDTA, 3 mM DTT, 0.05% NP-40 for 5 min at room
temperature. The reaction is initiated by the addition of pNPP (2 mM
final concentration) and run for 120 min at room temperature. Reactions
are quenched with 5 N NaOH. Absorbance at 405 nm is measured using any
standard 384 well plate reader.

[0098]PTP-1B.sub.[1-298] is expressed in E. coli BL21(DE3) containing
plasmids constructed using pET19b vectors (Novagen). The bacteria are
grown in minimal media using an "On Demand" Fed-batch strategy.
Typically, a 5.5 liter fermentation is initiated in Fed-batch mode and
grown overnight unattended at 37° C. Optical densities varied
between 20-24 OD600 and the cultures are induced at 30° C.
with IPTG to a final concentration of 0.5 mM. The bacterial cells are
harvested 8 hours later and yield 200-350 gm (wet weight). The cells are
frozen as pellets and stored at -80° C. until use. All steps are
performed at 4° C. unless noted. Cells (-15 g) are thawed briefly
at 37° C. and resuspended in 50 mL of lysis buffer containing 50
mM Tris-HCl, 150 mM NaCl, 5 mM DTT, pH 8.0 containing one tablet of
Complete (EDTA-free) protease cocktail (Boehringer Mannheim), 100 μM
PMSF and 100 μg/mL DNase I. The cells are lysed by sonication
(4×10 second burst, full power) using a Virsonic 60 (Virtus). The
pellet is collected at 35,000×g, resuspended in 25 mL of lysis
buffer using a Polytron and collected as before. The two supernatants are
combined and centrifuged for 30 min at 100,000×g. The soluble
lysate could be stored at this stage at -80° C. or used for
further purification. Diafiltration using a 10 kD MWCO membrane is used
to buffer exchange the protein and reduce the NaCl concentration prior to
cation exchange chromatography. Diafiltration buffer contained 50 mM MES,
75 mM NaCl, 5 mM DTT, pH 6.5. Soluble supernatant is then loaded onto a
POROS 20 SP (1×10 cm) column equilibrated with cation exchange
buffer (50 mM MES and 75 mM NaCl, pH 6.5) at a rate of 20 ml/min. An
analytical column (4.6×100 mm) is run in a similar fashion except
the flow rate was reduced to 10 mL/min. Protein is eluted from the column
using a linear salt gradient (75-500 mM NaCl in 25 CV). Fractions
containing PTP-1B.sub.[1-298] are identified and pooled according to
SDS-PAGE analyses. Final purification is performed using Sephacryl S-100
HR (Pharmacia). The column (2.6×35 cm) is equilibrated with 50 mM
HEPES, 100 mM NaCl, 3 mM DTT, pH 7.5 and run at a flow rate of 2 mL/min.
The final protein is pooled and concentrated to ˜5 mg/mL using an
Ultrafree-15 concentrator (Millipore) with a MWCO 10,000. The
concentrated protein is stored at -80° C. until use.

[0099]Competitive binding to the active site of the enzyme can be
determined as follows: Ligand binding is detected by acquiring
1H-15N HSQC spectra on 250 μL of 0.15 mM PTP-1B.sub.[1-298]
in the presence and absence of added compound (1-2 mM). The binding is
determined by the observation of 15N- or 1H-amide chemical
shift changes in two dimensional HSQC spectra upon the addition of a
compound to 15N-label protein. Because of the 15N spectral
editing, no signal from the ligand is observed, only protein signals.
Thus, binding can be detected at high compound concentrations. Compounds
which caused a pattern of chemical shift changes similar to the changes
seen with known active site binders are considered positive.

[0101]The 1H-15N HSQC NMR spectra are recorded at 20° C.,
on Bruker DRX500 or DMX600

[0102]NMR spectrometers. In all NMR experiments, pulsed field gradients
are applied to afford the suppression of solvent signal. Quadrature
detection in the indirectly detected dimensions is accomplished by using
the States-TPPI method. The data are processed using Bruker software and
analyzed using NMRCompass software (MSI) on Silicon Graphics computers.

[0103]To determine if a PTP inhibitor is useful for the treatment of
musculoskeletal disease, particularly muscle atrophy, the following in
vitro and animal model assays can be used.

Tissue Culture

[0104]C2C12 cells can be obtained from the American Type Tissue Culture
Bank and propagated in standard growth media containing 10% horse serum.
When cells reached 70% confluency the media is changed to differentiation
media containing 2% horse serum. Three days after start of
differentiation multinucleated myotubes should be present, with visible
striations, indicating differentiation. hGH can be used as a positive
control for activating the IGF-1 receptor, or alternatively, combined
with a PTP1B inhibitor to assess synergistic or additive effects.
Consequently, PTP1B inhibitors and/or hGH can be added to the media for
various times.

[0105]Myotube Diameter Myotube diameter can be assessed 24 hours after
addition of PTP1B inhibitor and/or hGH to myotube media. Cells are washed
in saline and fixed in gluteraldehyde. Images can be obtained on an
inverted microscope using the green fluorescent channel to visualize the
auto-fluorescence induced by the gluteraldehyde fixation. Images are
printed out at standard magnification and the sixty largest myotubes
measured at their largest diameter (as previously published). The fifty
largest myotubes in each group can be statistically compared using the
Kruskal-Wallis One Way Analysis on Ranks. Differences are considered
significant if p<0.05 and designated by an asterisk in FIG. 1.

[0106]pAKT assay Phosphorylation levels of AKT, a protein that is
phosphorylated when the IGF1 protein binds to its receptor, can be
assessed using a commercially available pAKT ELISA kit (Cell Signaling,
Pathscan 7160) and the corresponding total AKT ELISA kit (Cell Signaling,
Pathscan 7170), following manufacturer instructions.

[0108]PTP1B inhibitors and hGH hGH is Human Growth Hormone and it can be
purchased from Bachem H-3148 and added to C2C12 culture media or GH
expression vectors can be transfected into C2C12. Multiple PTP1B
inhibitors can be tested with or without hGH.

In Vivo Testing in Mouse Exercise Models of Hypertrophy

[0109]To determine whether a PTP inhibitor can act to increase skeletal
muscle mass under an exercise context that already leads to muscle
hypertrophy, one can subject treated and untreated animals to exercise
and determine whether animals receiving the PTP inhibitor have developed
larger muscles than untreated animals.

[0110]One model known in the art is based on the use of a voluntary
running wheel with user-variable loads (see, e.g., Konhilas et al., Am J
Physiol Heart Circ Physiol 289:H455-H465, 2005). The voluntary cage wheel
eliminates physical and psychological insults that are common in forced
exercised models, and are therefore more appropriate for evaluating
candidate drugs that are used in relatively healthy individuals for whom
increases in muscle mass is desirable.

[0111]Any suitable mouse strain can be used. For example, male C57BI/6J
mice can be randomly assigned to experimental (e.g., receiving PTP
inhibitor) and control groups. Animals are individually housed in a cage
containing an exercise wheel; sedentary control animals are housed in
identical cages without a wheel. The exercise wheels are described in
Allen et al., J Appl Physiol 90:1900-1908, 2001. Briefly, the system
consists of an 11.5 cm-diameter wheel with a 5.0 cm-wide running surface
(model 6208, Petsmart, Phoenix, Ariz.) equipped with a digital magnetic
counter (model BC 600, Sigma Sport, Olney, Ill.) that is activated by
wheel rotation. In addition, each wheel is engineered with a resistance
mechanism allowing adjustment of the load. This is accomplished by
attaching stainless steel fishing line to the cage top and wrapping the
wire around an immovable pulley that is secured to the cage wheel at the
axis of rotation so as to not contribute to the wheel load. The wire is
again secured to the cage top with a spring and screw. This design
permits fine adjustments of the wheel load, which is evenly distributed
throughout the rotation of the wheel. Daily exercise values for time and
distance run are recorded for each exercised animal throughout the
duration of the exercise period. All animals are given water and standard
hard rodent chow ad libitum. Voluntary running (cage wheel exposure) can
begin at an average age of about 12 weeks for all groups. Each group
continues running under varying resistance, depending on experimental
group, for 50 days until the animals are about 19 weeks of age. The load
on the wheel is determined by hanging known weights on the wheel until
the wheel was slightly displaced. All exercise groups begin with no load
on the cage wheel for the first week. However, the "no-load" condition is
actually 2 g, which is determined as the load necessary to maintain wheel
inertia and frictional load. Considering a wheel acclimatization period
of 1 week, wheel loads can be changed at one-week intervals, except for
higher loads, which can be changed after 2 weeks. The range of loads can
be anywhere from 2 g to up to 12 g. Exercised and sedentary control
animals are euthanized by cervical dislocation under inhaled anesthesia
immediately after the end of the specific exercise period. Body mass is
measured, and specific muscles are rapidly excised, washed, and frozen
for histological or biochemical assays at a future date.

[0113]In this in vivo model, lack of PTP1b can be tested for the ability
to maintain muscle mass under conditions that generally reduce muscle
mass.

[0114]Mice Heterozygous PTP1B null mice can be purchased from Deltagen
(San Carlos, Calif., USA) and mated to produce offspring that are null,
heterozygous, or wild-type litter mates. Mice are housed under ACUC
protocol 06 MG 0144 and maintained with food and water ad libitum in a 12
hour light cycle. Mice can be genotyped by PCR on tail biopsies.

[0115]Denervation The right sciatic nerve is resected during deep
anesthesia under ACUC protocol 06 MG 0189. Briefly, anesthesia is induced
using isofluorane inhalation, the right leg shaved and sterilized. An
incision is then made through the skin of the lateral right leg and the
sciatic nerve visualized. The nerve is cut and a 0.3 to 0.5 section
removed to prevent reattachment. The incision was closed with wound clips
and the mice returned to their cages for recovery from anesthesia. The
contralateral leg is unperturbed and serves as internal control. Mice are
euthanized 14 days after denervation surgery and muscles and other
tissues isolated for further processing.

[0116]Muscle and Tissue Weight The following tissues can be dissected from
PTP1B knock out knock out (KO), heterozygous (HET), and wild-type (WT)
mice 14 days after denervation of the right hind limb: left and right
tibialis anterior muscles, left and right extensor digitorum longus
muscles, left and right soleus muscles, left and right gastrocnemius
muscles, heart, liver, spleen, epididimal white adipose tissue, brown
adipose tissue, and blood for serum isolation. Each tissue is freed from
connective tissue and weighed, before being snap frozen for further
analysis to be completed.

Experimental Set-Up and Analysis

[0117]The effect of PTP1B inhibition on muscle disease can be measured, as
described above, in an in vitro model system of skeletal muscle atrophy,
using the C2C12 cell line, and in an in vivo model of skeletal muscle
atrophy, using PTP1B wild type, heterozygous, and homozygous null mice in
combination with denervation-induced skeletal muscle atrophy.

[0118]Treatment of C2C12 myotubes with PTP1B inhibitors can result in an
increase in myotube size, when the diameter of the fifty largest myotubes
is measured.

[0119]When IGF1 alone is added to C2C12 myotubes media at a concentration
of 10 ng/ml, myotubes can be significantly hypertrophied. Addition of hGH
alone can also cause a significant increase in C2C12 myotube diameter. A
PTP inhibitor can result in an increase in myotube diameter that is
significantly bigger than the diameter of untreated myotubes. There might
not be a statistical significance between cells treated with either IGF1,
hGH, or an inhibitor individually, but when myotubes are treated with
both IGF1 or hGH and an inhibitor simultaneously, this could result in a
significant increase in myotube diameter when compared to the
singly-treated cells. Such a result would indicate that the IGF1 pathway
and a PTP inhibitor act at least additively and potentially
synergistically to produce larger myotubes and therefore indicate that
hGH and a PTP inhibitor can be co-administered to a mammal to increase
muscle mass or to treat muscle atrophy. Alternatively, assay results can
indicate that a PTP inhibitor is active alone, in which case use of the
inhibitor in monotherapy to increase muscle mass or to treat muscle
atrophy is indicated.

[0120]PTP1B null mice can be used to test whether absence of PTP1B can
prevent or ameliorate skeletal muscle atrophy. Fourteen days after
denervation of the right hind limb, muscle weight of denervated muscles
is compared to contralateral muscles from the control leg (wet muscle
weight is normalized to individual body weight). Using this animal model
of skeletal muscle atrophy, there is significant sparing of muscles in
heterozygous and knock-out mice. WT mice lose about 40% of gastrocnemius
muscle mass, compared with a 30% loss in heterozygous mice and 20% in
homozygous null mice. Half of the denervation-induced muscle atrophy is
prevented in KO gastrocnemius muscle compared to WT gastrocnemius muscle.

[0121]Phosphorylation of AKT is a downstream event of IGF1R
phosphorylation. Levels of AKT phosphorylation can be used as a read-out
of activation of the IGF1 pathway in C2C12 myotubes treated with a PTP
inhibitor +/-IGF1 or +/-hGH for one hour. A PTP inhibitor alone can
increase phosphorylation levels of AKT by for example at least 50% (e.g.,
65%). hGH treatment is known to cause AKT phosphorylation in C2C12, but
treatment of hGH with a PTP inhibitor can further increases AKT
phosphorylation above that induced by hGH alone. Treatment with a PTP
inhibitor can therefore increase activation of the IGF1 pathway, possibly
resulting in a significant increase in myotube diameter in the manner
described above.

[0122]Results from experiments such as described above can indicate that
PTP inhibitors, particularly PTP1B inhibitors, increase levels of pAKT,
which in turn result in a physiological increase in myotube diameter.
Observations can include: [0123]A PTP inhibitor causes a significant
increase in C2C12 myotube diameter by itself and acts at least additively
with hGH in media to further increase myotube size. [0124]A PTP inhibitor
causes a significant increase in C2C12 myotubes when compared to
untreated myotubes.

[0125]Furthermore, in vivo atrophy study using PTP1B KO and WT mice with
denervation-induced muscle atrophy can show that inhibition of PTP1B
prevents skeletal muscle atrophy.

[0126]Provided that a PTP inhibitor exhibits in vitro or in vivo activity
for increasing muscle mass, e.g., by way of modulating the IGF1 signaling
pathway at the level of AKT phosphorylation, such PTP inhibitors would
then also be useful for other diseases known to be amenable to IGF1 or
human Growth Hormone treatment, such as dwarfism, low bone density or
mineral content, osteoporosis or short stature.

[0127]The methods of the invention can be practiced with
1,1-dioxo-1,2,5-thiadiazolidin-3-one derivatives as described in the
categories below.

Category 1 PTP Inhibitors

[0128]The methods of the present invention can be practiced with the
compounds of the formula

##STR00001##

whereinQ combined together with the carbon atoms to which it is attached
form an aromatic, or a partially or fully saturated nonaromatic 5- to
8-membered carbocyclic or heterocyclic ring; [0129]R1 is hydrogen,
--C(O)R6, --C(O)NR7R8 or --C(O)OR9 in whichR6
and R7 are, independently from each other, hydrogen, cycloalkyl,
aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally
substituted with one to four substituents selected from the group
consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy,
amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl;R8
and R9 are, independently from each other, cycloalkyl, aryl,
heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with
one to four substituents selected from the group consisting of halogen,
cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino,
dialkylamino, aryl, aryloxy and heterocyclyl;R2, R3, R4
and R5 are, independently from each other, hydrogen, hydroxy,
halogen, cyano, nitro, alkoxy, alkylthio, alkylthiono, sulfonyl, free or
esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino,
cycloalkyl, aryl, heterocyclyl, alkenyl, alkynyl or (C1-8)alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl,
acyloxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl,
sulfonamido, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl,
aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy,
heterocyclyl and heterocyclyloxy; orR2 and R3 combined are
alkylene which together with the ring atoms to which they are attached
form a 3- to 7-membered fused ring; orR2 and R3 combined are
alkylene which together with the carbon atom to which they are attached
form a 3- to 7-membered spirocyclic ring;or a pharmaceutically acceptable
salt thereof.

[0136]Preferred are compounds of formula (IB) wherein [0137]R2 is
--Y--(CH2)n--CR10R11--(CH2)m--X in which
[0138]Y is oxygen or S(O)q in which q is zero or an integer of 1 or
2; or [0139]Y is trans CH═CH; or [0140]Y is absent; [0141]n is an
integer from 1 to 6; [0142]R10 and R11 are, independently from
each other, hydrogen or lower alkyl; orR10 and R11 combined are
alkylene which together with the carbon atom to which they are attached
form a 3- to 7-membered ring; [0143]m is zero or an integer of 1 or 2;X
is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl,
cyano, trifluoromethyl, free or esterified carboxy, monocyclic aryl or
heterocyclyl;or a pharmaceutically acceptable salt thereof.

[0146]Further preferred are also compounds of formula (IB) wherein
[0147]n is an integer of 2 or 3; [0148]R10 and R11 are,
independently from each other, hydrogen or lower alkyl; [0149]m is zero
or 1;X is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified
carboxy, monocyclic aryl or heterocyclyl;or a pharmaceutically acceptable
salt thereof.

[0152]Even more preferred are compounds of formula (IB) wherein [0153]n
is 3; [0154]R10 and R11 are lower alkyl; [0155]m is zero or 1;
[0156]X is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0159]Especially preferred are compounds of formula (IB) wherein
[0160]R1 is hydrogen or --C(O)R6 in which R6 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0161]Preferred are also compounds in the A group having the formula

##STR00004##

wherein [0162]R1 is hydrogen or --C(O)R6,
--C(O)NR7R6 or --C(O)OR9 in whichR6 and R7 are,
independently from each other, hydrogen, cycloalkyl, aryl, heterocyclyl,
aralkyl, heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R8 and R9 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2, R3, R4 and R5 are, independently
from each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy,
alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,
sulfamoyl, optionally substituted amino, cycloalkyl, aryl, heterocyclyl,
alkenyl, alkynyl or (C1-8)alkyl optionally substituted with one to
four substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2 and R3
combined are alkylene which together with the ring atoms to which they
are attached form a 3- to 7-membered fused ring; orR2 and R3
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered spirocyclic ring;p is zero or 1;or a
pharmaceutically acceptable salt thereof.

[0173]Preferred are also compounds of formula (ID), designated as the B
group, wherein

R2 and R3 are, independently from each other, hydrogen, halogen
or (C1-4)alkyl optionally substituted by at least one halogen;or a
pharmaceutically acceptable salt thereof.

[0174]Preferred are compounds in the B group wherein [0175]R1 is
hydrogen or --C(O)R6 in which R6 is monocyclic aryl;or a
pharmaceutically acceptable salt thereof.

[0176]Preferred are also compounds of formula (ID), designated as the C
group, wherein

R2 and R3 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 5-membered spirocyclic
ring;or a pharmaceutically acceptable salt thereof.

[0177]Preferred are compounds in the C group, wherein [0178]R1 is
hydrogen or --C(O)R6 in which R6 is monocyclic aryl;or a
pharmaceutically acceptable salt thereof.

[0179]Preferred are also compounds of formula (ID), designated as the D
group, wherein [0180]R2 is
--Y--(CH2)n--CR10R11--(CH2)m--X in which
[0181]Y is oxygen or S(O)q in which q is zero or an integer of 1 or
2; or [0182]Y is trans CH═CH; or [0183]Y is absent; [0184]n is an
integer from 1 to 6; [0185]R10 and R11 are, independently from
each other, hydrogen or lower alkyl; orR10 and R11 combined are
alkylene which together with the carbon atom to which they are attached
form a 3- to 7-membered ring; [0186]m is zero or an integer of 1 or 2;X
is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl,
cyano, trifluoromethyl, free or esterified carboxy, monocyclic aryl or
heterocyclyl;or a pharmaceutically acceptable salt thereof.

[0187]Preferred are compounds in the D group wherein [0188]R3 is
hydrogen;or a pharmaceutically acceptable salt thereof.

[0189]Further preferred are compounds in the D group wherein [0190]n is
an integer of 2 or 3; [0191]R10 and R11 are, independently from
each other, hydrogen or lower alkyl; [0192]m is zero or 1; [0193]X is
hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy,
monocyclic aryl or heterocyclyl;or a pharmaceutically acceptable salt
thereof.

[0194]More preferred are compounds in the D group wherein [0195]Y is
absent;or a pharmaceutically acceptable salt thereof.

[0196]Even more preferred are compounds in the D group wherein [0197]n
is 3; [0198]R10 and R11 are lower alkyl; [0199]m is zero or 1;
[0200]X is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0201]Most preferred are compounds in the D group wherein [0202]R10
and R11 are methyl;or a pharmaceutically acceptable salt thereof.

[0203]Especially preferred are compounds in the D group wherein
[0204]R1 is hydrogen or --C(O)Re in which R6 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0348]The methods of the invention can be practiced with the compounds of
the formula

##STR00006##

wherein [0349]R1 is hydrogen, --C(O)R2, --C(O)NR3R4
or --C(O)OR5 in whichR2 and R3 are, independently from
each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R4 and R5 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;U, W and V are, independently from each other, hydrogen,
hydroxy, halogen, cyano, nitro, alkoxy, alkylthio, alkylthiono, sulfonyl,
free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted
amino, cycloalkyl, aryl, aryloxy, arylthio, heterocyclyl,
heterocycloyloxy, alkenyl, alkynyl or (C1-5)alkyl optionally
substituted with one to four substituents selected from the group
consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy,
alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, acylamino,
carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido,
sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy,
arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and
heterocyclyloxy; orU and W combined together with the carbon atoms to
which they are attached form an optionally substituted aromatic, or a
partially or fully saturated nonaromatic 5- to 8-membered carbocyclic or
heterocyclic ring; orW and V combined together with the carbon atoms to
which they are attached form an optionally substituted aromatic, or
partially or fully saturated nonaromatic 5- to 8-membered carbocyclic or
heterocyclic ring;or a pharmaceutically acceptable salt thereof.

[0350]Preferred are the compounds of formula (I) wherein

U and W combined together with the carbon atoms to which they are attached
form an optionally substituted aromatic, or a partially or fully
saturated nonaromatic 5- to 8-membered carbocyclic or heterocyclic ring;V
is hydrogen;or a pharmaceutically acceptable salt thereof.

[0351]Further preferred are the compounds of formula (I) having the
formula

##STR00007##

[0352]whereinQa combined together with the carbon atoms to which it
is attached form an aromatic, or a partially or fully saturated
nonaromatic 5- to 8-membered carbocyclic or heterocyclic ring;
[0353]R1 is hydrogen, --C(O)R2, --C(O)NR3R4 or
--C(O)OR5 in whichR2 and R3 are, independently from each
other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R4 and R5 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2a, R3a, R4a and R5a are, independently
from each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy,
alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,
sulfamoyl, optionally substituted amino, cycloalkyl, aryl, heterocyclyl,
alkenyl, alkynyl or (C1-8)alkyl optionally substituted with one to
four substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2a and R3a
combined are alkylene which together with the ring atoms to which they
are attached form a 3- to 7-membered fused ring; orR2a and R3a
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered spirocyclic ring;or a
pharmaceutically acceptable salt thereof.

[0354]Preferred are compounds of formula (Ia), designated as the A group,
wherein

Qa combined together with the carbon atoms to which it is attached
form an aromatic, or a partially or fully saturated 5- to 6-membered
carbocyclic ring;or a pharmaceutically acceptable salt thereof.

[0362]Preferred are compounds of formula (Ia2) wherein
[0363]R2a is
--Ya--(CH2)n--CR6aR7a--(CH2)m--Xa
in which [0364]Ya is oxygen or S(O)q in which q is zero or an
integer of 1 or 2; or [0365]Ya is trans CH═CH; or [0366]Ya
is absent; [0367]n is an integer from 1 to 6; [0368]R6a and R7a
are, independently from each other, hydrogen or lower alkyl; orR6a
and R7a combined are alkylene which together with the carbon atom to
which they are attached form a 3- to 7-membered ring; [0369]m is zero
or an integer of 1 or 2;Xa is hydroxy, alkoxy, cycloalkyl,
cycloalkoxy, acyl, acyloxy, carbamoyl, cyano, trifluoromethyl, free or
esterified carboxy, monocyclic aryl or heterocyclyl;or a pharmaceutically
acceptable salt thereof.

[0372]Further preferred are also compounds of formula (Ia2) wherein
[0373]n is an integer of 2 or 3; [0374]R6a and R7a are,
independently from each other, hydrogen or lower alkyl; [0375]m is zero
or 1;Xa is hydroxy, carbamoyl, cyano, trifluoromethyl, free or
esterified carboxy, monocyclic aryl or heterocyclyl;or a pharmaceutically
acceptable salt thereof.

[0378]Even more preferred are compounds of formula (Ia2) wherein
[0379]n is 3; [0380]R6a and R7a are lower alkyl; [0381]m is
zero or 1; [0382]Xa is hydroxy, cyano or free or esterified
carboxy;or a pharmaceutically acceptable salt thereof.

[0385]Especially preferred are compounds of formula (Ia2) wherein
[0386]R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0387]Preferred are also compounds in the A group having the formula

##STR00010##

wherein [0388]R1 is hydrogen, --C(O)R2, --C(O)NR3R4
or --C(O)OR5 in whichR2 and R3 are, independently from
each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R4 and R5 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2a, R3a, R4a and R5a are, independently
from each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy,
alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,
sulfamoyl, optionally substituted amino, cycloalkyl, aryl, heterocyclyl,
alkenyl, alkynyl or (C1-8)alkyl optionally substituted with one to
four substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2a and R3a
combined are alkylene which together with the ring atoms to which they
are attached form a 3- to 7-membered fused ring; orR2a and R3a
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered spirocyclic ring;p is zero or 1;or a
pharmaceutically acceptable salt thereof.

[0399]Preferred are also compounds of formula (Ia4), designated as
the B group, wherein

R2a and R3a are, independently from each other, hydrogen,
halogen or (C1-4)alkyl optionally substituted by at least one
halogen;or a pharmaceutically acceptable salt thereof.

[0400]Preferred are compounds in the B group wherein [0401]R1 is
hydrogen or --C(O)R2 in which R2 is monocyclic aryl;or a
pharmaceutically acceptable salt thereof.

[0402]Preferred are also compounds of formula (Ia4), designated as
the C group, wherein

R2a and R3a combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 5-membered spirocyclic
ring;or a pharmaceutically acceptable salt thereof.

[0403]Preferred are compounds in the C group, wherein [0404]R1 is
hydrogen or --C(O)R2 in which R2 is monocyclic aryl;

[0405]or a pharmaceutically acceptable salt thereof.

[0406]Preferred are also compounds of formula (Ia4), designated as
the D group, wherein [0407]R2a is
--Ya--(CH2)a--CR6aR7a(CH2)m--Xa
in which [0408]Ya is oxygen or S(O)q in which q is zero or an
integer of 1 or 2; or [0409]Ya is trans CH═CH; or [0410]Ya
is absent; [0411]n is an integer from 1 to 6; [0412]R6a and R7a
are, independently from each other, hydrogen or lower alkyl; orR6a
and R7a combined are alkylene which together with the carbon atom to
which they are attached form a 3- to 7-membered ring; [0413]m is zero
or an integer of 1 or 2;Xa is hydroxy, alkoxy, cycloalkyl,
cycloalkoxy, acyl, acyloxy, carbamoyl, cyano, trifluoromethyl, free or
esterified carboxy, monocyclic aryl or heterocyclyl;or a pharmaceutically
acceptable salt thereof.

[0414]Preferred are compounds in the D group wherein [0415]R3a is
hydrogen;or a pharmaceutically acceptable salt thereof.

[0416]Further preferred are compounds in the D group wherein [0417]n is
an integer of 2 or 3; [0418]R6a and R7a are, independently from
each other, hydrogen or lower alkyl; [0419]m is zero or 1; [0420]Xa
is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified
carboxy, monocyclic aryl or heterocyclyl;or a pharmaceutically acceptable
salt thereof.

[0421]More preferred are compounds in the D group wherein [0422]Ya
is absent;or a pharmaceutically acceptable salt thereof.

[0423]Even more preferred are compounds in the D group wherein [0424]n
is 3; [0425]R6a and R7a are lower alkyl; [0426]m is zero or 1;
[0427]Xa is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0428]Most preferred are compounds in the D group wherein [0429]R6a
and R7a are methyl;or a pharmaceutically acceptable salt thereof.

[0430]Especially preferred are compounds in the D group wherein
[0431]R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0432]Preferred are also the compounds of formula (I), wherein [0433]U
and V are hydrogen; [0434]W is aryloxy, arylthio or methyl substituted
with monocyclic aryl;or a pharmaceutically acceptable salt thereof.

[0435]Further preferred are also the compounds of formula (I) having the
formula

##STR00012##

[0436]wherein [0437]R1 is hydrogen, --C(O)R2,
--C(O)NR3R4 or --C(O)OR5 in whichR2 and R3 are,
independently from each other, hydrogen, cycloalkyl, aryl, heterocyclyl,
aralkyl, heteroaralkyl or alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, cycloalkyl,
cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino,
aryl, aryloxy and heterocyclyl;R4 and R5 are, independently
from each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2b, R3b and R4b are, independently from each
other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio,
alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,
optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl,
alkynyl or (C1-5)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2b and R3b
combined are alkylene which together with the ring atoms to which they
are attached form a 5- to 7-membered fused ring provided R2 and
R3 are attached to carbon atoms adjacent to each other; orR2b
and R3b combined together with the carbon atom to which they are
attached form a fused 5- to 6-membered aromatic or heteroaromatic ring
provided R2 and R3 are attached to carbon atoms adjacent to
each other;Xb is hydrogen, fluoro, cyano, or free or esterified
carboxy; orXb is --NR5bC(O)R6b, --NR5bC(O)OR7b,
--NR5bS(O)2R8b, --(CH2)rS(O)2R9b,
--OS(O)2R10b or --OsC(O)NR11bR12b in which
[0438]R5b is hydrogen, lower alkyl, acyl, alkoxycarbonyl or
sulfonyl;R6b, R7b, R8b, R9b and R10b are,
independently from each other, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR6b, R8b
and R9b are, independently from each other, --NR13bR14b in
which R13b and R14b are, independently from each other,
hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl; orR13b
and R14b combined are alkylene which together with the nitrogen atom
to which they are attached form a 4- to 7-membered ring;R11b and
R12b are, independently from each other, hydrogen, alkyl,
cycloalkyl, aralkyl, aryl or heterocyclyl; orR11b and R12b
combined are alkylene which together with the nitrogen atom to which they
are attached form a 4- to 7-membered ring;r and s are, independently from
each other, zero or an integer of 1; orC--Xb is replaced by
nitrogen;

Yb is O, S or CH2;

[0439]or a pharmaceutically acceptable salt thereof.

[0440]Preferred are the compounds of formula (Ib) wherein

Yb is CH2,

[0441]or a pharmaceutically acceptable salt thereof.

[0442]Further preferred are the compounds of formula (Ib) having the
formula

##STR00013##

whereinR1 is hydrogen, --C(O)R2, --C(O)NR3R4 or
--C(O)OR5 in whichR2 and R3 are, independently from each
other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R4 and R5 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2b, R3b and R4b are, independently from each
other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio,
alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,
optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl,
alkynyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2b and R3b
combined are alkylene which together with the ring atoms to which they
are attached form a 5- to 7-membered fused ring; orR2b and R3b
combined together with the carbon atom to which they are attached form a
fused 5- to 6-membered aromatic or heteroaromatic ring;Xb is cyano;
orXb is --NR5bC(O)R6b, --NR5bC(O)OR7b,
--NR5bS(O)2R8b, --(CH2)rS(O)2R9b or
--OS(O)2R10b in which [0443]R5b is hydrogen or lower
alkyl;R6b, R7b, R8b, R13 and R10b are,
independently from each other, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR6b, R8b
and R9b are, independently from each other, --NR13bR14b in
whichR13b and R14b are, independently from each other,
hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl; orR13b
and R14b combined are alkylene which together with the nitrogen atom
to which they are attached form a 4- to 7-membered ring;r is zero;
orC--Xb is replaced by nitrogen;or a pharmaceutically acceptable
salt thereof.

[0453]Preferred are the compounds in the G group, designated as the H
group, wherein

U is --Yc--(CH2)p--CR2cR3c--(CH2)t--X.s-
ub.c in whichYc is oxygen or S(O)v in which v is zero or an
integer of 1 or 2; or

Yc is C≡C; or

[0454]Yc is absent;p and t are, independently from each other, zero
or an integer from 1 to 8;R2 and R3, are, independently from
each other, hydrogen or lower alkyl; orR2 and R3, combined are
alkylene which together with the carbon atom to which they are attached
form a 3- to 7-membered ring;Xc is hydroxy, alkoxy, cycloalkyl,
cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino,
cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl,
monocyclic aryl or monocyclic aryloxy;or a pharmaceutically acceptable
salt thereof.

[0455]Preferred are the compounds in the H group wherein

R2, and Ric are hydrogen;or a pharmaceutically acceptable salt
thereof.

[0456]Further preferred are the compounds in the H group wherein

p is zero or an integer from 1 to 3;t is zero or 1;R2 and R3
are, independently from each other, hydrogen or lower alkyl;Xc is
hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy,
heterocyclyl, monocyclic aryl or monocyclic aryloxy;or a pharmaceutically
acceptable salt thereof.

[0457]Especially preferred are the compounds in the H group, designated as
the I group, wherein

Yc is C≡C; or

[0458]Yc is absent;or a pharmaceutically acceptable salt thereof.

[0459]Preferred are the compounds in the I group wherein

Yc is absent;p is an integer of 5 or 6;t is zero or 1;R2 and
R3 are lower alkyl;Xc is hydroxy, cyano or free or esterified
carboxy;or a pharmaceutically acceptable salt thereof.

[0460]Further preferred are the compounds in the I group wherein

R2c and R3c are methyl;or a pharmaceutically acceptable salt
thereof.

[0461]Especially preferred are the compounds in the I group wherein

R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0462]Preferred are also the compounds in the I group, designated as the J
group, wherein

Yc is absent;p is an integer of 4 or 5;t is zero;R2c and
R3C are hydrogen;Xc is monocyclic aryloxy;or a pharmaceutically
acceptable salt thereof.

[0463]Preferred are the compounds in the J group wherein

R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0464]Preferred are also the compounds in the J group, designated as the K
group, wherein

Yc is CE C;

[0465]p is an integer of 2 or 3;t is zero;R2c and R3c are
hydrogen;Xc is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0466]Preferred are the compounds in the K group wherein

R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0467]Preferred are also the compounds in the G group, designated as the L
group, wherein

R7c is
--(CH2)p--CR10cR11c--(CH2)rZc in
whichp and t are, independently from each other, zero or an integer from
1 to 6;R10c and R11c are, independently from each other,
hydrogen or lower alkyl; orR10c and R11c combined are alkylene
which together with the carbon atom to which they are attached form a 3-
to 7-membered ring;Zc is hydroxy, alkoxy, cycloalkyl, cycloalkoxy,
acyl, acyloxy, carbamoyl, optionally substituted amino, cyano,
trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic
aryl or monocyclic aryloxy;or a pharmaceutically acceptable salt thereof.

[0476]Further preferred are the compounds of formula (Ic2) wherein

p is an integer from 1 to 3;t is zero or 1;R10c and R11c are,
independently from each other, hydrogen or lower alkyl;Zc is
hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy,
heterocyclyl, monocyclic aryl or monocyclic aryloxy;or a pharmaceutically
acceptable salt thereof.

[0477]More preferred are the compounds of formula (Ic2) wherein

R10c and R11c are hydrogen;Zc is hydroxy, cyano or free or
esterified carboxy;or a pharmaceutically acceptable salt thereof.

[0478]Most preferred are the compounds of formula (Ic2) wherein

R1 is hydrogen or --C(O)R2 in which R2 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0511]Preferred are the compounds of formula (I), designated as the A
group, wherein

Q is --Y--(CH2)n--CR8R9--(CH2)m--X in whichY
is oxygen or S(O)q in which q is zero or an integer of 1 or 2; or

Y is C≡C; or

[0512]Y is absent;n and m are, independently from each other, zero or an
integer from 1 to 8;R8 and R9 are, independently from each
other, hydrogen or lower alkyl; orR8 and R9 combined are
alkylene which together with the carbon atom to which they are attached
form a 3- to 7-membered ring;X is hydroxy, alkoxy, cycloalkyl,
cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino,
cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl,
monocyclic aryl or monocyclic aryloxy;or a pharmaceutically acceptable
salt thereof.

[0513]Preferred are the compounds in the A group wherein

R2 and R3 are hydrogen;or a pharmaceutically acceptable salt
thereof.

[0514]Further preferred are the compounds in the A group wherein

n is zero or an integer from 1 to 3;m is zero or 1;R8 and R9
are, independently from each other, hydrogen or lower alkyl;X is hydroxy,
carbamoyl, cyano, trifluoromethyl, free or esterified carboxy,
heterocyclyl, monocyclic aryl or monocyclic aryloxy;or a pharmaceutically
acceptable salt thereof.

[0515]Especially preferred are the compounds in the A group, designated as
the B group, wherein

Y is C≡C; or

[0516]Y is absent;or a pharmaceutically acceptable salt thereof.

[0517]Preferred are the compounds in the B group wherein

Y is absent;n is an integer of 5 or 6;m is zero or 1;R8 and R9
are lower alkyl;X is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0518]Further preferred are the compounds in the B group wherein

R8 and R9 are methyl;or a pharmaceutically acceptable salt
thereof.

[0519]Especially preferred are the compounds in the B group wherein

R1 is hydrogen or --C(O)R4 in which R4 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0520]Preferred are also the compounds in the B group, designated as the C
group, wherein

Y is absent;n is an integer of 4 or 5;m is zero;R8 and R9 are
hydrogen;X is monocyclic aryloxy;or a pharmaceutically acceptable salt
thereof.

[0521]Preferred are the compounds in the C group wherein

R1 is hydrogen or --C(O)R4 in which R4 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0522]Preferred are also the compounds in the B group, designated as the D
group, wherein

Y is C≡C;

[0523]n is an integer of 2 or 3;m is zero;R8 and R9 are
hydrogen;X is hydroxy, cyano or free or esterified carboxy;or a
pharmaceutically acceptable salt thereof.

[0524]Preferred are the compounds in the D group wherein

R1 is hydrogen or --C(O)R4 in which R4 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0525]Preferred are the compounds of formula (I), designated as the E
group, wherein

R13 is --(CH2)n--CR16R17--(CH2)m-Z in
whichn and m are, independently from each other, zero or an integer from
1 to 6;R16 and R17 are, independently from each other, hydrogen
or lower alkyl; orR16 and R17 combined are alkylene which
together with the carbon atom to which they are attached form a 3- to
7-membered ring;Z is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl,
acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl,
free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic
aryloxy;or a pharmaceutically acceptable salt thereof.

[0534]Further preferred are the compounds of formula (IC) wherein

n is an integer from 1 to 3;m is zero or 1;R16 and R17 are,
independently from each other, hydrogen or lower alkyl;Z is hydroxy,
carbamoyl, cyano, trifluoromethyl, free or esterified carboxy,
heterocyclyl, monocyclic aryl or monocyclic aryloxy;or a pharmaceutically
acceptable salt thereof.

[0535]More preferred are the compounds of formula (IC) wherein

R16 and R17 are hydrogen;Z is hydroxy, cyano or free or
esterified carboxy;or a pharmaceutically acceptable salt thereof.

[0536]Most preferred are the compounds of formula (IC) wherein

R1 is hydrogen or --C(O)R4 in which R4 is monocyclic
aryl;or a pharmaceutically acceptable salt thereof.

[0640]The methods of the invention can be practiced with the compounds of
the formula

##STR00021##

whereinR1 is hydrogen, --C(O)R5, --C(O)NR6R7 or
--C(O)OR8 in whichR5 and R6 are, independently from each
other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R7 and R8 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2, R3 and R4 are, independently from each
other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio,
alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,
optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl,
alkynyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2 and R3
combined are alkylene which together with the ring atoms to which they
are attached form a 5- to 7-membered fused ring provided R2 and
R3 are attached to carbon atoms adjacent to each other; orR2
and R3 combined together with the carbon atom to which they are
attached form a fused 5- to 6-membered aromatic or heteroaromatic ring
provided R2 and R3 are attached to carbon atoms adjacent to
each other;X is hydrogen, fluoro, cyano, or free or esterified carboxy;
orX is --NR9C(O)R10, --NR8C(O)OR11,
--NR8S(O)2R12, --(CH2)mS(O)2R13,
--OS(O)2R14 or --OnC(O)NR15R18 in which
[0641]R9 is hydrogen, lower alkyl, acyl, alkoxycarbonyl or
sulfonyl;R10, R11, R12, R13 and R14 are,
independently from each other, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR10, R12
and R13 are, independently from each other, --NR17R18 in
whichR17 and R18 are, independently from each other, hydrogen,
alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl; orR17 and R18
combined are alkylene which together with the nitrogen atom to which they
are attached form a 4- to 7-membered ring;R15 and R16 are,
independently from each other, hydrogen, alkyl, cycloalkyl, aralkyl, aryl
or heterocyclyl; orR15 and R16 combined are alkylene which
together with the nitrogen atom to which they are attached form a 4- to
7-membered ring;m and n are, independently from each other, zero or an
integer of 1; orC--X is replaced by nitrogen;

Y is CH2, O or S;

[0642]or a pharmaceutically acceptable salt thereof.

[0643]Preferred are the compounds of formula (I) wherein

Y is CH2;

[0644]or a pharmaceutically acceptable salt thereof.

[0645]Further preferred are the compounds of formula (I) having the
formula

##STR00022##

whereinR1 is hydrogen, --C(O)R5, --C(O)NR6R7 or
--C(O)OR8 in whichR5 and R6 are, independently from each
other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl
or alkyl optionally substituted with one to four substituents selected
from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R7 and R8 are, independently from each other,
cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl
optionally substituted with one to four substituents selected from the
group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy,
alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and
heterocyclyl;R2, R3 and R4 are, independently from each
other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio,
alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,
optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl,
alkynyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR2 and R3
combined are alkylene which together with the ring atoms to which they
are attached form a 5- to 7-membered fused ring; orR2 and R3
combined together with the carbon atom to which they are attached form a
fused 5- to 6-membered aromatic or heteroaromatic ring;X is cyano; orX is
--NR9C(O)R10, --NR9C(O)OR11,
--NR9S(O)2R12, --(CH2)mS(O)2R13 or
--OS(O)2R14 in which [0646]R9 is hydrogen or lower
alkyl;R10, R11, R12, R13 and R14 are,
independently from each other, cycloalkyl, aryl, heterocyclyl, aralkyl,
heteroaralkyl or (C1-8)alkyl optionally substituted with one to four
substituents selected from the group consisting of halogen, hydroxy,
cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino,
alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,
alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or
esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy,
heteroaralkoxy, heterocyclyl and heterocyclyloxy; orR10, R12
and R13 are, independently from each other, --NR17R18 in
whichR17 and R18 are, independently from each other, hydrogen,
alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl; orR17 and R18
combined are alkylene which together with the nitrogen atom to which they
are attached form a 4- to 7-membered ring;m is zero; orC--X is replaced
by nitrogen;or a pharmaceutically acceptable salt thereof.

[0800]The methods of the invention can be practiced with the compounds of
the formula

##STR00023##

wherein

Q is:

i) --X, or

[0801]ii)-Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X in whichY is oxygen or S(O)q in which q is zero or an integer
of 1 or 2; or

Y is --C≡C-- or --C═C--; or

[0802]Y is cyclopropyl orY is absent;n and m are, independently from each
other, zero or an integer from 1 to 8;R8 and R9 are,
independently from each other, hydrogen, hydroxyl, alkoxy, alkanoyl,
alkanoylamino, alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl,
carbamoyl, aryl, or alkyl; orR8 and R9 combined are alkylene
which together with the carbon atom to which they are attached form a 3-
to 7-membered ring;p is zero or an integer selected from 1 or 2Z is
absent;

Z is --C(O)--O--; or

Z is --C(O)--; or

[0803]Z is --C(O)--NRα-alkylene- or --C(O)--NRα-alkylene-O--,
wherein Rα is H or lower alkyl; orZ is
--CO--NRα-(CH2)n'--(CR8'R9')p'--(CH2)-
m'--, or
--C(O)--NRα-(CH2)n'--(CR8'R9')p'--(CH2)m'--O--, wherein p' is zero or an integer of 1, n' and m' are,
independently from each other, zero or an integer from 1 to 8, R8'
and R9' are, independently from each other, hydrogen or lower alkyl,
Rα is H or lower alkyl; orZ is --NRα'-C(O)--, or
--NRα'-C(O)--O--, wherein Rα' is H or lower alkyl, or
Rα' and R9 combined are alkylene which together with the
carbon atom to which they are attached form a 3- to 7-membered ring; or

Z is --C(O)--NH--NH--C(O)--O--; or

Z is --S(O)2--, or --S(O)--; or

[0804]Z is --NRβ-S(O)2--, wherein Rβ is H, lower alkyl, or
Rβ and R9 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 7-membered ring; or

Z is --NH--S(O)2--NH--C(O)--O--; or

[0805]Z is --NRγ-C(O)--NRγ'-; wherein Rγ' is H, alkyl,
aryl, heterocyclyl or lower alkoxy and Rγ is H, lower alkyl, or
Rγ and R9 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 7-membered ring; or
Rγ' and X combined are alkylene which together with the carbon atom
to which they are attached form a 3- to 7-membered ring orZ is
--NRτ-C(O)--NH--S(O)2--, wherein Rτ is H or lower alkyl,X is
hydrogen, hydroxy, NH2, halogen, alkoxy, alkylthio, alkyl,
--S(O)--OH, alkyl, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl,
optionally substituted amino, cyano, trifluoromethyl, free or esterified
carboxy, heterocyclyl, heterocyclooxy, heteroaryl, heteroaralkyl, aryl,
aralkyl, aralkoxy, aryloxy, aralkylthio, arylthio;R1 is hydrogen,
--C(O)R4, --C(O)NR5R6 or --C(O)OR7 in whichR4
and R5 are, independently from each other, hydrogen, cycloalkyl,
aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally
substituted with one to four substituents selected from the group
consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy,
amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl;R6
and R7 are, independently from each other, cycloalkyl, aryl,
heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with
one to four substituents selected from the group consisting of halogen,
cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino,
dialkylamino, aryl, aryloxy and heterocyclyl;R2 and R3 are,
independently from each other, hydrogen, halogen, (C1-3)alkyl or
(C1-3)alkoxy;or a pharmaceutically acceptable salt thereof,and
wherein n+m+p is >1 or is 0, when X is aryl, and Y and Z are
absent,n+m+p is not 0 when X is --O-aryl, and Y and Z are absent, orn+m+p
is not 0 when X is --S-aryl, and Y and Z are absent, orn+m+p is not 0
when X is --CH2-aryl, and Y and Z are absent, orn+m+p is not 0 when
X is aryl, Z is absent and Y is --O-- or Y is --S--, orwherein Q cannot
be --CH2-aryl, --S-aryl or --O-aryl.

[0806]Preferably, the orientation of the Z function is with the X group on
the right side of the listed function -Z→X e.g. Z is
--NRα'-C(O)-- means Z is --NRα'-C(O)--X.

[0807]Preferred are the compounds of formula (I), designated as the ALPHA
group, wherein

Q is: --Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X
in whichY is oxygen or S(O)q in which q is zero or an integer of 1
or 2; or

Y is --C≡C-- or --C═C--; or

[0808]Y is cyclopropyl orY is absent;n and m are, independently from each
other, zero or an integer from 1 to 8;R8 and R9 are,
independently from each other, hydrogen, hydroxyl, alkoxy, alkanoyl,
alkanoylamino, alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl,
carbamoyl, aryl, or alkyl; orR8 and R9 combined are alkylene
which together with the carbon atom to which they are attached form a 3-
to 7-membered ring;p is zero or an integer selected from 1 or 2Z is
absent;

Z is --C(O)--O--; or

Z is --C(O)--; or

[0809]Z is --C(O)--NRα-alkylene- or --C(O)--NRα-alkylene-O--,
wherein Rα is H or lower alkyl; orZ is
--CO--NRα-(CH2)n'--(CR8R9')p'--(CH2).-
sub.m'--, or
--C(O)--NRα-(CH2)n'--(CR8'R9')p'--(CH2)m'--O--, wherein p' is zero or an integer of 1, n' and m' are,
independently from each other, zero or an integer from 1 to 8, R8'
and R9' are, independently from each other, hydrogen or lower alkyl,
Rα is H or lower alkyl; orZ is --NRα'-C(O)--, or
--NRα'-C(O)--O--, wherein Rα' is H or lower alkyl, or
Rα' and R9 combined are alkylene which together with the
carbon atom to which they are attached form a 3- to 7-membered ring; or

Z is --C(O)--NH--NH--C(O)--O--; or

Z is --S(O)2--, or --S(O)--; or

[0810]Z is --NRβ-S(O)2--, wherein R13 is H, lower alkyl, or
Rβ and R9 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 7-membered ring; or

Z is --NH--S(O)2--NH--C(O)--O--; or

[0811]Z is --NRγ--C(O)--NRγ'; wherein Rγ' is H, alkyl,
aryl, heterocyclyl, or lower alkoxy and Rγ is H, lower alkyl, or
Rγ and R9 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 7-membered ring; or
Rγ' and X combined are alkylene which together with the carbon atom
to which they are attached form a 3- to 7-membered ring orZ is
NRτ-C(O)--NH--S(O)2--, wherein Rτ is H or lower alkyl,X is
hydrogen, hydroxy, NH2, halogen, alkoxy, alkylthio, alkyl,
--S(O)--OH, alkyl, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl,
optionally substituted amino, cyano, trifluoromethyl, free or esterified
carboxy, heterocyclyl, heterocyclooxy, heteroaryl, heteroaralkyl, aryl,
aralkyl, aralkoxy, aryloxy, aralkylthio, arylthio;R1 is hydrogen,
--C(O)R4, --C(O)NR5R6 or --C(O)OR7 in which R4
and R5 are, independently from each other, hydrogen, cycloalkyl,
aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally
substituted with one to four substituents selected from the group
consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy,
amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl;R6
and R7 are, independently from each other, cycloalkyl, aryl,
heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with
one to four substituents selected from the group consisting of halogen,
cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino,
dialkylamino, aryl, aryloxy and heterocyclyl;R2 and R3 are,
independently from each other, hydrogen, halogen, (C1-3)alkyl or
(C1-3)alkoxy;or a pharmaceutically acceptable salt thereof,and
wherein n+m+p is >1 or is 0, when X is aryl, and Y and Z are
absent,n+m+p is not 0 when X is --O-aryl, and Y and Z are absent, orn+m+p
is not 0 when X is --S-aryl, and Y and Z are absent, orn+m+p is not 0
when X is --CH2-aryl, and Y and Z are absent, orn+m+p is not 0 when
X is aryl, Z is absent and Y is --O-- or Y is --S--, orwherein Q cannot
be --CH2-aryl, --S-aryl or --O-aryl.

[0812]Preferably, the orientation of the Z function is with the X group on
the right side of the listed function -Z→X e.g. Z is
--NRα'-C(O)-- means Z is --NRα'-C(O)--X.

n is zero or an integer from 1 to 4;m is zero or an integer from 1 to 4;p
is zero or 1;or a pharmaceutically acceptable salt thereof.

[0818]Especially preferred are the compounds in the ALPHA group, wherein

m+n+p is between 0 and 7 or preferably between 0 and 5,or a
pharmaceutically acceptable salt thereof.

[0819]Preferred are the compounds of formula (I), designated as the A
group, wherein

Q is --Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X,
in whichY is oxygen or S(O)q in which q is zero or an integer of 1
or 2; or

Y is --C≡C-- or --C═C--; or

[0820]Y is cyclopropyl; orY is absent;n and m are, independently from each
other, zero or an integer from 1 to 8;R8 and R9 are,
independently from each other, hydrogen, hydroxyl, alkoxy, alkanoyl,
alkanoylamino, alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl,
carbamoyl, aryl, or alkyl;p is zero or an integer selected from 1 or 2Z
is absent;

n is zero or an integer from 1 to 3;m is zero or an integer from 1 to 3;p
is zero or 1;or a pharmaceutically acceptable salt thereof.

[0838]Especially preferred are the compounds in the B group, wherein

m+n+p is between 0 and 6 or preferably 0 and 4,or a pharmaceutically
acceptable salt thereof.

[0839]Other preferred compounds are the compounds in the B group, wherein

m+n is between 0 and 6 or preferably 0 and 4, andp is 0,or a
pharmaceutically acceptable salt thereof.

[0840]Other preferred compounds are the compounds in the B group, wherein

X is selected from phenyl or heteroaryl, preferably unsubstituted or
substituted by at least one substituent e.g. one or two, which is
preferably a substituent selected from carboxy, carbamoyl, and lower
alkyl,or a pharmaceutically acceptable salt thereof.

[0841]Other preferred compounds are the compounds in the B group, wherein

m+n is 1, 2 or 3, preferably 1 or 2,m+m+p is preferably 2 or 3,p is 1 or
0, andX is cycloalkyl, heterocyclyl, heteroaryl, or aryl, preferably
unsubstituted or substituted by at least one substituent e.g. one or two,
which is preferably a substituent selected from sulfonamido, carboxy,
carbamoyl, and lower alkyl,or a pharmaceutically acceptable salt thereof.

[0842]Other preferred compounds are the compounds in the B group, wherein

m+n is 1, 2 or 3, preferably 1 or 2,m+n+p is 2, 3 or 4, preferably 2 or
3,p is 1 or 0, andX is aryl, preferably unsubstituted or substituted by
at least one substituent e.g. one or two, which is preferably a
substituent selected from sulfonamido, carboxy, carbamoyl, and lower
alkyl,or a pharmaceutically acceptable salt thereof.

[0843]Other preferred compounds are the compounds in the B group, wherein

m+n is 1, 2 or 3, preferably 1 or 2,p is 1 or 0, andX is "amide" type
heterocyclyl, cycloalkyl substituted by at least one substituent e.g. one
or two, which is preferably sulfonamide, or aryl substituted by at least
one substituent e.g. one or two, which is preferably sulfonamidoor a
pharmaceutically acceptable salt thereof.

[0844]Preferred are the compounds of formula (I), designated as the C,
wherein

Q is --Y--(CH2)n--(CR8R9)p--(CF12)m-Z-X-
, in whichY is oxygen or S(O)q in which q is zero or an integer of 1
or 2; or

Y is --C≡C-- or --C═C--; or

[0845]Y is absent;n and m are, independently from each other, zero or an
integer from 1 to 8;R8 and R9 are, independently from each
other, hydrogen, hydroxyl, alkoxy, alkanoyl, alkanoylamino,
alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl, carbamoyl, aryl, or
alkyl; orR8 and R9 combined are alkylene which together with
the carbon atom to which they are attached form a 3- to 7-membered ring;p
is zero or an integer selected from 1 or 2Z is --CO--NRα-alkylene-
or --CO--NRα-alkylene-O--, wherein Rα is H or lower alkyl;
orZ is --CO--NRα-(CH2)n'--(CR8'R9')p'--(CH-
2)m'--,
or--CO--NRα-(CH2)n'--(CR8'R9')p'--(CH2)m'--O--,wherein p' is zero or an integer of 1, n' and m' are
independently from each other, zero or an integer from 1 to 8, R8'
and R9' are, independently from each other, hydrogen or lower alkyl,
Rα is H or lower alkyl; orZ is --NRα'-CO--, or
--NRα'-CO--O--, wherein Rα' is, H or lower alkyl, or
Rα' and R9 combined are alkylene which together with the
carbon atom to which they are attached form a 3- to 7-membered ring; or

n is zero or an integer from 1 to 3;m is zero or an integer from 1 to 3;p
is zero or 1;or a pharmaceutically acceptable salt thereof.

[0853]Especially preferred are the compounds in the C group, wherein

m+n+p is between 0 and 6 or preferably between 0 and 4,or a
pharmaceutically acceptable salt thereof.

[0854]Other preferred compounds are the compounds in the C group, wherein

m+n+p is between 1 and 3 (i.e. 1, 2 or 3)m+n is between 1 and 3 (i.e. 1, 2
or 3) and p is 0m+n+p is between 1 and 3 (i.e. 1, 2 or 3) and p is 1m is
0, n is between 1 and 2 (i.e. 1, or 2) and p is 1or a pharmaceutically
acceptable salt thereof.

[0855]Especially preferred are the compounds in the C group, wherein

n' and m' are independently from each other, zero or an integer from 1 to
6, andp' is zero or an integer of 1, or a pharmaceutically acceptable
salt thereof.

[0856]Especially preferred are the compounds in the C group, wherein

p'+n'+m' is comprised between zero and 5, or between 3 and 5 i.e. 3, 4 or
5, or a pharmaceutically acceptable salt thereof.

[0857]Especially preferred are the compounds in the C group, wherein

n' and m' are independently from each other, zero or an integer from 1 to
6, preferably from 1 to 4,or a pharmaceutically acceptable salt thereof.

[0858]Other preferred compounds are the compounds in the C group, wherein

n'+m' is between 0 and 5, or between 3 and 5, preferably 4, andp' is 0,or
a pharmaceutically acceptable salt thereof.

X is aryl or heteroaryl, or a pharmaceutically acceptable salt thereof.

[0865]Especially preferred are the compounds in the D group, wherein

X is aryl substituted by an "amide" type heterocyclyl, or a
pharmaceutically acceptable salt thereof.

[0866]Preferred are the compounds of formula (I), designated as the E
group, wherein

Q is --Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X,
in whichY is oxygen or S(O)q in which q is zero or an integer of 1
or 2; or

Y is --C≡C-- or --C═C--; or

[0867]Y is absent;n and m are, independently from each other, zero or an
integer from 1 to 8;R8 and R9 are, independently from each
other, hydrogen, hydroxyl, alkoxy, alkanoyl, alkanoylamino,
alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl, carbamoyl, aryl, or
alkyl; orR8 and R9 combined are alkylene which together with
the carbon atom to which they are attached form a 3- to 7-membered ring;p
is zero or an integer selected from 1 or 2

Z is --SO2--, or --SO--; or

[0868]Z is --NRβ-SO2--, wherein Rβ is H, lower alkyl, or
Rβ and R9 combined are alkylene which together with the carbon
atom to which they are attached form a 3- to 7-membered ring preferably
5-, 6- or 7-membered ring; or

R8 and R9 are, independently from each other, hydrogen, aralkyl,
heteroaryl, heterocyclyl, heterocyclyl, carbamoyl; orR8 and R9
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered ring;or a pharmaceutically
acceptable salt thereof.

n is zero or an integer from 1 to 4;m is zero or an integer from 1 to 4;p
is zero or 1;or a pharmaceutically acceptable salt thereof.

[0876]Especially preferred are the compounds in the E group, wherein

m+n+p is between 0 and 7 or preferably between 0 and 5,or a
pharmaceutically acceptable salt thereof.

[0877]Other preferred compounds are the compounds in the E group, wherein

i) m+n+p is 2 or 3, orii) m+n is 2 or 3, and p is 0, oriii) n is 1 or 2, m
is 0 or 1, and p is 1 when Rβ and R9 combined are alkylene
which together with the carbon atom to which they are attached form a 5-,
6- or 7-membered ringor a pharmaceutically acceptable salt thereof.

[0878]Other preferred compounds are the compounds in the E group, wherein

m+n is 1 or 2, m is 0 or 1, and p is 1, orn is 1 or 2, m is 0 or 1, and p
is 1 when R8 is hydrogen and R9 is selected from aralkyl,
heteroaryl, heterocyclyl, heterocyclyl, or carbamoyl;or a
pharmaceutically acceptable salt thereof.

[0879]Other preferred compounds are the compounds in the E group, wherein

X is selected from phenyl, biphenyl, benzyl, lower alkyl, methyl
substituted by on or two phenyl, ethyl substituted by one or two pheny,
or methyl substituted by cycloalkyl

[0880]Preferred are the compounds of formula (I), designated as the F
group, wherein

Q is --Y--(CH2)n--(CR8R9)p--(CH2)m-Z-X,
in whichY is oxygen or S(O)q in which q is zero or an integer of 1
or 2; or

Y is --C≡C-- or --C═C--; or

[0881]Y is absent;n and m are, independently from each other, zero or an
integer from 1 to 8;R8 and R9 are, independently from each
other, hydrogen, hydroxyl, alkoxy, alkanoyl, alkanoylamino,
alkoxycarbonyl, aralkyl, heteroaryl, heterocyclyl, carbamoyl, aryl, or
alkyl; orR8 and R9 combined are alkylene which together with
the carbon atom to which they are attached form a 3- to 7-membered ring;p
is zero or an integer selected from 1 or 2Z is
--NRγ-CO--NRγ'--; wherein Rγ' is H, alkyl, aryl,
heterocyclyl, or lower alkoxy and Rγ is H, lower alkyl, or Rγ
and R9 combined are alkylene which together with the carbon atom to
which they are attached form a 3- to 7-membered ring; or Rγ' and X
combined are alkylene which together with the carbon atom to which they
are attached form a 3- to 7-membered ring; orZ is
--NRτ-CO--NH--SO2--, wherein Rτ is H or lower alkyl,X is
hydrogen, hydroxy, NH2, halogen, alkoxy, alkylthio, --SO--OH, alkyl,
cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted
amino, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl,
heterocyclooxy, heteroaryl, heteroaralkyl, aryl, aralkyl, aralkoxy,
aryloxy, aralkylthio, arylthio;or a pharmaceutically acceptable salt
thereof.